Wikipedia

Tretinoin

For the isomer of tretinoin used primarily to treat more severe acne, seeIsotretinoin.For all-trans-retinoic acid as the metabolite of vitamin A, seeRetinoic acid.

Tretinoin,also known asall-transretinoic acid(ATRA), is amedicationused for the treatment ofacneandacute promyelocytic leukemia.[8][9][10]For acne, it is applied to the skin as a cream, gel or ointment.[10]For acute promyelocytic leukemia, it is effective only when the RARA-PML fusion mutation is present[11]and is taken by mouth for up to three months.[8]Topical tretinoin is also the most extensively investigated retinoid therapy forphotoaging.[12]

Tretinoin
Clinical data
PronunciationSee pronunciation note
Trade namesRetin-A, Avita, Renova, others
Other namesATRA
AHFS/Drugs.comMonograph
TopicalMonograph
MedlinePlusa608032
License data
Pregnancy
category
  • AU:X (High risk)/ (Oral); D (Topical)[1][2]
Routes of
administration		Topical,by mouth
ATC code
Legal status
Legal status
Pharmacokineticdata
Protein binding> 95%
Eliminationhalf-life0.5–2 hours
Identifiers
  • (2E,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.005.573Edit this at Wikidata
Chemical and physical data
FormulaC20H28O2
Molar mass300.442g·mol−1
3D model (JSmol)
Melting point180 °C (356 °F)
  • CC1=C(C(CCC1)(C)C)C=CC(=CC=CC(=CC(=O)O)C)C
  • InChI=1S/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8+,16-14+checkY
  • Key:SHGAZHPCJJPHSC-YCNIQYBTSA-NcheckY
(verify)

Common side effects when used as a cream are limited to the skin and include skin redness, peeling, and sun sensitivity.[10]When taken by mouth, side effects includehypertriglyceridemia,hypercholesterolemia,shortness of breath,headache, numbness, depression, skin dryness, itchiness, hair loss, vomiting, muscle pains, and vision changes.[8]Other severe side effects includehigh white blood cell countsandblood clots.[8]Use duringpregnancyis contraindicated due to the risk of birth defects.[8][1]It is in theretinoidfamily of medications.[9]

Tretinoin was patented in 1957 and approved for medical use in 1962.[13]It is on theWorld Health Organization's List of Essential Medicines.[14]Tretinoin is available as ageneric medication.[15]In 2022, it was the 238th most commonly prescribed medication in the United States, with more than 1million prescriptions.[16][17]

Medical uses

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Skin use

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Acne

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Tretinoin is most commonly used to treatacne,[6]both inflammatory and noninflammatory. Multiple studies support the efficacy of topical retinoids in the treatment of acne vulgaris.[18][19]It is sometimes used in conjunction with other topical acne medications to enhance their penetration.[20]In addition to treating active acne, retinoids accelerate the resolution of acne-inducedpostinflammatory hyperpigmentation.[21]It is also useful as maintenance therapy for people who have responded well to their initial treatment, reducing the prolonged use of antibiotics for acne.[22]

Photoaging

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Photoagingis premature skin aging resulting from prolonged and repeated exposure to solar radiation. Features of photoaging include fine and coarse wrinkles, changes in skin pigmentation, and loss of elasticity. In human skin, topical retinoids increase collagen production, induce epidermal hyperplasia, and decreasekeratinocyteandmelanocyteatypia. Topical tretinoin is the most extensively investigated retinoid therapy for photoaging.[23]Topical tretinoin can be used for mild to severe photoaging in people of all skin types. Several weeks or months of use are typically required before improvement is appreciated. Although it has only been studied for up to two years, it may be continued indefinitely. A long-term maintenance regimen with a lower concentration or less frequent application may be an alternative to continued use.[24]

Leukemia

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Tretinoin is used to induce remission in people withacute promyelocytic leukemia(APL) who have a mutation (the t(15;17) translocation that gives rise to the PML::RARα fusion gene). It is not used for maintenance therapy.[5][25][26]

Tretinoin is not effective for the treatment of non-APL forms ofAcute Myeloid Leukemia[27]or other forms of leukemia. Preclinical studies and clinical data analysis suggest that retinoic acid promotes the growth ofT-cell acute lymphoblastic leukemia.[28]

Side effects

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Dermatology

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Topical tretinoin is for use only on the skin and should not be applied to eyes or mucosal tissues. Common side effects include skin irritation, redness, swelling, and blistering.[6]If irritation is a problem, a decrease in the frequency of application to every other or every third night can be considered, and the frequency of application can be increased as tolerance improves. The fine skin flaking that is often seen can be gently exfoliated with a washcloth. A non-comedogenic facial moisturizer can also be applied if needed. Delaying the application of the retinoid for at least 20 minutes after washing and drying the face may also be helpful. Topical retinoids are not true photosensitizing drugs, but people using topical retinoids have described symptoms of increased sun sensitivity. This is thought to be due to the thinning of thestratum corneumleading to a decreased barrier against ultraviolet light exposure, as well as an enhanced sensitivity due to the presence of cutaneous irritation.[29]

Acute Promyelocytic Leukemia

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The oral form of the drug hasboxed warningsconcerning the risks ofretinoic acid syndromeandleukocytosis.[5]Other significant side effects include a risk ofthrombosis,benign intracranial hypertensionin children, high lipids (hypercholesterolemiaand/orhypertriglyceridemia), and liver damage.[5]

There are many significant side effects from this drug that include malaise (66%), shivering (63%), hemorrhage (60%), infections (58%), peripheral edema (52%), pain (37%), chest discomfort (32%), edema (29%), disseminated intravascular coagulation (26%), weight increase (23%), injection site reactions (17%), anorexia (17%), weight decrease (17%), and myalgia (14%).[5]

Respiratory side effects usually signifyretinoic acidsyndrome, and include upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), and expiratory wheezing (14%), and many others at less than 10%.[5]Around 23% of people taking the drug have reported earache or a feeling of fullness in their ears.[5]Gastrointestinal disorders include bleeding (34%), abdominal pain (31%), diarrhea (23%), constipation (17%), dyspepsia (14%), and swollen belly (11%) and many others at less than 10%.[5]

Cardiovascular side effects include arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%),phlebitis(11%), and cardiac failure (6%) and for 3% of patients: cardiac arrest, myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy.[5]

In the nervous system, side effects include dizziness (20%),paresthesias(17%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%), and many others at less than 10% frequency.[5]

In the urinary system, side effects includechronic kidney disease(11%) and several others at less than 10% frequency.[5]

Mechanism of action

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For its use in Acute Promyelocytic Leukemia, tretinoin causes the RARA:PML fusion oncogene to degrade, resulting in the loss of the key driver oncogene.[30]This degradation allows the blasts to mature and results in dramatic responses. This response is typically short-lived as Cyp26 genes are rapidly upregulated to degrade tretinoin. The RARA:PML oncogene is not present in other cancer types, thus explaining why tretinoin and otherretinoidshave not been effective across hundreds of different trials.[31]

For its use in acne, tretinoin (along with other retinoids) are vitamin A derivatives that act by binding to two nuclear receptor families within keratinocytes: theretinoic acid receptors(RAR) and theretinoid X receptors(RXR).[21]These events contribute to the normalization of follicular keratinization and decreased cohesiveness ofkeratinocytes,resulting in reduced follicular occlusion and microcomedone formation.[32]The retinoid-receptor complex competes for coactivator proteins of AP-1, a key transcription factor involved in inflammation.[21]Retinoids also down-regulate expression of toll-like receptor (TLR)-2, which has been implicated in the inflammatory response in acne.[33]Moreover, tretinoin and retinoids may enhance the penetration of other topical acne medications.[20]

The combination of the 10%benzoyl peroxideand light results in more than 50% degradation of tretinoin in about 2 hours and 95% in 24 hours.[34]This lack of stability in the presence of light and oxidizing agents has led to the development of novel formulations of the drug. Whenmicroencapsulatedtretinoin is exposed to benzoyl peroxide and light only 1% degradation takes place in about 4 hours and only 13% after 24 hours.[35]

The biological mechanism behind triglyceride and cholesterol elevations remains under investigation.[citation needed]

Synthesis

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Biosynthetic pathway of tretinon

All-trans retinoic acid is produced by the body from dietary factors including retinol, retinyl esters orbeta-carotene.The beta-carotene is first cleaved bybeta-carotene 15-15'-monooxygenaseto retinol which is subsequently oxidized by RDH and ALDH enzymes to produce all-trans retinoic acid (seeretinoic acid). Tretinoin is produced synthetically using standard industrial practices.[36]

History

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Tretinoin was co-developed for its use in acne byJames FultonandAlbert Kligmanwhen they were atUniversity of Pennsylvaniain the 1960s.[37][38]Phase I trials, the first conducted on human subjects, were performed on inmates atHolmesburg Prisonduring a long-running regime of non-therapeutic and unethicaltesting on prison inmates at Holmesburg.[39][40]The University of Pennsylvania held the patent for Retin-A, which it licensed to pharmaceutical companies.[38]

Treatment of acute promyelocytic leukemia was first introduced atRuijin Hospitalin Shanghai byWang Zhenyiin a 1988 clinical trial.[41]

Etymology

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The origin of the nametretinoinis uncertain,[42][43]although several sources agree (one with probability,[42]< one with asserted certainty[44]) that it probably comes fromtrans-+retinoic[acid]+-in,which is plausible given that tretinoin is theall-trans isomerofretinoic acid.The nameisotretinoinis the same roottretinoinplus the prefixiso-.Regarding pronunciation, the following variants apply equally to bothtretinoinandisotretinoin.Given thatretinoicis pronounced/ˌrɛtɪˈnoʊɪk/,[43][44][42][45]it isnaturalthat/ˌtrɛtɪˈnoʊɪn/is a commonly heard pronunciation. Dictionary transcriptions also include/ˌtrɪˈtɪnoʊɪn/(tri-TIN-oh-in)[43][42]and/ˈtrɛtɪnɔɪn/.[44][45]

Hair loss

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Tretinoin has been explored as a treatment for hair loss, potentially as a way to increase the ability ofminoxidil(by acting as an enzyme and accelerating the production of minoxidil sulfate) to penetrate the scalp, but the evidence is weak and contradictory.[46][47]

References

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